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Mammalian esophageal stratified tissue homeostasis is maintained distinctively by the epithelial pluripotent p63+Sox2+ and p63−Sox2+ cell populations

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Abstract

Self-renewing, damage–repair and differentiation of mammalian stratified squamous epithelia are subject to tissue homeostasis, but the regulation mechanisms remain elusive. Here, we investigate the esophageal squamous epithelial tissue homeostasis in vitro and in vivo. We establish a rat esophageal organoid (rEO) in vitro system and show that the landscapes of rEO formation, development and maturation trajectories can mimic those of rat esophageal epithelia in vivo. Single-cell RNA sequencing (scRNA-seq), snapshot immunostaining and functional analyses of stratified “matured” rEOs define that the epithelial pluripotent stem cell determinants, p63 and Sox2, play crucial but distinctive roles for regulating mammalian esophageal tissue homeostasis. We identify two cell populations, p63+Sox2+ and p63−Sox2+, of which the p63+Sox2+ population presented at the basal layer is the cells of origin required for esophageal epithelial stemness maintenance and proliferation, whereas the p63−Sox2+ population presented at the suprabasal layers is the cells of origin having a dual role for esophageal epithelial differentiation (differentiation-prone fate) and rapid tissue damage–repair responses (proliferation-prone fate). Given the fact that p63 and Sox2 are developmental lineage oncogenes and commonly overexpressed in ESCC tissues, p63−Sox2+ population could not be detected in organoids formed by esophageal squamous cell carcinoma (ESCC) cell lines. Taken together, these findings reveal that the tissue homeostasis is maintained distinctively by p63 and/or Sox2-dependent cell lineage populations required for the tissue renewing, damage–repair and protection of carcinogenesis in mammalian esophagi.

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Data availability

Data will be made available upon reasonable request.

Abbreviations

rEO:

Rat esophageal organoid

scRNA-seq:

Single-cell RNA sequencing

ESCC:

Esophageal squamous cell carcinoma

RES:

Respiratory–esophageal separation

SRY:

Sex-determining region Y

HDs:

Hemidesmosomes

mEOs:

Mammalian esophageal organoids

PSCs:

Pluripotent stem cells

EoE:

Eosinophilic esophagitis

SOE:

Overexpression of Sox2

hTERT:

Human telomere reverse transcriptase

RNE-D3:

Immortalized rat normal esophageal epithelial D3 cell line

RESCs:

Rat esophageal squamous carcinoma cell lines

FBS:

Fetal bovine serum

OFR:

Organoid formation rate

PCs:

Primary rat esophageal squamous keratinocyte cells

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Acknowledgements

During this study (in 2019), Prof. Shih-Hsin Lu passed away. We all miss him.

Funding

This work was supported by the National Natural Science Foundation of China (NSFC) (Gran number 81972572 to Wei Jiang) and the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (CIFMS) (Grant number 2021-I2M-1-014 to Xiying Yu).

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  1. Xiaohong Yu and Hui Yuan contributed equally to this work.

Authors and Affiliations

  1. Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China

    Xiaohong Yu, Hui Yuan, Yanan Yang, Wei Zheng, Xuejing Zheng, Shih-Hsin Lu, Wei Jiang & Xiying Yu

  2. State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China

    Xiaohong Yu, Hui Yuan, Yanan Yang, Wei Zheng, Shih-Hsin Lu, Wei Jiang & Xiying Yu

  3. Departments of Orthopedics, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China

    Xuejing Zheng

  4. Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China

    Shih-Hsin Lu, Wei Jiang & Xiying Yu

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Contributions

All the authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Xiaohong Yu and HY. The first draft of the manuscript was written by Xiying Yu and WJ. All the authors commented on previous versions of the manuscript. All the authors read and approved the final manuscript.

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Yu, X., Yuan, H., Yang, Y. et al. Mammalian esophageal stratified tissue homeostasis is maintained distinctively by the epithelial pluripotent p63+Sox2+ and p63−Sox2+ cell populations. Cell. Mol. Life Sci. 80, 305 (2023). https://doi.org/10.1007/s00018-023-04952-z

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